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Assessment of Kidney Function in Mouse Models of Glomerular Disease
Published on: June 30, 2018
Dapagliflozin in focal segmental glomerulosclerosis: a combined human-rodent pilot study
Harindra Rajasekeran1,2, Heather N Reich1, Michelle A Hladunewich3
1Department of Medicine, Division of Nephrology, University Health Network, University of Toronto , Toronto, Ontario , Canada.
Abstract:
Focal segmental glomerulosclerosis (FSGS) is an important cause of nondiabetic chronic kidney disease (CKD). Sodium-glucose cotransporter 2 inhibition (SGLT2i) therapy attenuates the progression of diabetic nephropathy, but it remains unclear whether SGLT2i provides renoprotection in nondiabetic CKD such as FSGS. The primary aim of this pilot study was to determine the effect of 8 wk of dapagliflozin on glomerular filtration rate (GFR) in humans and in experimental FSGS. Secondary end points were related to changes in renal hemodynamic function, proteinuria, and blood pressure (BP). GFR (inulin) and renal plasma flow (para-aminohippurate), proteinuria, and BP were measured in patients with FSGS ( n = 10), and similar parameters were measured in subtotally nephrectomized (SNx) rats. In response to dapagliflozin, changes in GFR, renal plasma flow, and 24-h urine protein excretion were not statistically significant in humans or rats. Systolic BP (SBP) decreased in SNx rats (196 ± 26 vs. 165 ± 33 mmHg; P < 0.001), whereas changes were not statistically significant in humans (SBP 112.7 ± 8.5 to 112.8 ± 11.2 mmHg, diastolic BP 71.8 ± 6.5 to 69.6 ± 8.4 mmHg; P = not significant), although hematocrit increased (0.40 ± 0.05 to 0.42 ± 0.05%; P = 0.03). In archival kidney tissue from a separate patient cohort, renal parenchymal SGLT2 mRNA expression was decreased in individuals with FSGS compared with controls. Short-term treatment with the SGLT2i dapagliflozin did not modify renal hemodynamic function or attenuate proteinuria in humans or in experimental FSGS. This may be related to downregulation of renal SGLT2 expression. Studies examining the impact of SGLT2i on markers of kidney disease in patients with other causes of nondiabetic CKD are needed.
Insights
Sodium-glucose cotransporter 2 inhibition (SGLT2i) did not improve kidney function or reduce proteinuria in focal segmental glomerulosclerosis (FSGS) patients or in experimental models. Downregulated renal SGLT2 expression may explain these findings in nondiabetic kidney disease.
Area of Science:
- Nephrology
- Pharmacology
Background:
- Focal segmental glomerulosclerosis (FSGS) is a leading cause of nondiabetic chronic kidney disease (CKD).
- Sodium-glucose cotransporter 2 inhibitors (SGLT2i) show efficacy in diabetic nephropathy, but their role in nondiabetic CKD, like FSGS, is not well-established.
Purpose of the Study:
- To investigate the short-term effects of dapagliflozin, an SGLT2 inhibitor, on glomerular filtration rate (GFR) and other renal parameters in patients with FSGS and in an experimental rat model of FSGS.
- To explore the potential impact of SGLT2 expression levels in FSGS kidneys.
Main Methods:
- A pilot study involving 10 patients with FSGS and subtotally nephrectomized (SNx) rats treated with dapagliflozin for 8 weeks.
- Measurements included GFR, renal plasma flow, proteinuria, and blood pressure. Renal SGLT2 mRNA expression was analyzed in archival kidney tissue from FSGS patients and controls.
Main Results:
- Dapagliflozin did not significantly alter GFR, renal plasma flow, or 24-hour urine protein excretion in either humans or rats.
- Systolic blood pressure decreased significantly in SNx rats, but not in human patients. Hematocrit increased in human patients.
- Renal SGLT2 mRNA expression was found to be decreased in individuals with FSGS compared to controls.
Conclusions:
- Short-term dapagliflozin treatment did not demonstrate significant renoprotective effects or reduce proteinuria in human or experimental FSGS.
- Reduced renal SGLT2 expression in FSGS may contribute to the lack of response to SGLT2 inhibitors.
- Further research is warranted to evaluate SGLT2 inhibitors in other forms of nondiabetic CKD.
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